1. Field of the Invention
The present invention relates generally to the fields of Otolaryngology, Gastroenterology, Anesthesiology, Pulmonology and critical care medicine, and more particularly, the fields of detection and diagnosis of esophageal and extraesophageal gastric reflux (EEGR).
2. Description of Related Art
Gastric reflux, and especially EEGR, influences the development, duration and/or outcome of most major airway (i.e. the laryngopharynx, tracheobronchial tree and lung) diseases (Koufman 1991). It has also been suggested that EEGR is a causal factor of asthma, chronic obstructive pulmonary disease, sudden infant death syndrome (SIDS) and laryngeal carcinogenesis (Baccino et al., 1988; Herbst et al., 1979; Paton et al., 1989; Morrison 1988; Ward and Hanson 1988; Koufman 1991).
Gastroesophageal reflux (GER) refers to the backflow of gastric contents into the esophagus. Some GER is normal; however, in individuals with excessive reflux, either in amount or in duration, GER causes significant suffering and tissue damage and is termed gastroesophageal reflux disease (GERD). GERD has a relatively broad spectrum of clinical manifestations but is essentially defined by the development of "peptic esophagitis" (esophageal inflammation, even ulceration, stricture, metaplasia, and neoplasia, as the result of excessive contact of the esophageal lining with gastric acid and pepsin, the principal digestive enzyme of the stomach).
It is estimated that 10% of all Americans have symptoms of heartburn and regurgitation daily and 30% have symptoms less frequently (Castell et al. 1987), but estimates of the number of Americans with reflux-related laryngeal, voice and airway disorders remains unknown, because people with EEGR often do not have esophagitis or heartburn (Koufman 1991). Thus, although it has been reported that two-thirds of patients with laryngeal and voice disorders have EEGR as either the primary causal agent or a significant etiological cofactor, the prevalence of these EEGR-related conditions remains unknown. It is estimated that EEGR may affect up to 50% of adult Americans over 40 years of age.
Yet the epidemiologies and natural histories of GERD remain incompletely understood because of a lack of sensitive and accurate diagnostic tools for detecting and distinguishing GERD from EEGR and other diseases of the esophagus, throat and airway. Gastroenterologists and otolaryngologists are currently forced to make diagnoses based on the principal clinical symptoms, e.g. heartburn for GERD and for hoarseness EEGR. However, less than half of all patients with EEGR into the laryngeal and pharyngeal regions (i.e. the throat), as documented by pH monitoring, complain of heartburn or regurgitation (Ossakow et al. 1987; Koufman et al 1988; Koufman 1991; Koufman 1993; Koufman 1996; Wiener et al. 1986; Wiener et al. 1987; Wiener et al. 1989). Thus, the principal difference in symptoms between EEGR and GERD patients appears to be that EEGR patients infrequently have heartburn, the primary symptom of esophagitis.
Patients with EEGR usually complain of throat symptoms such as hoarseness, a sensation of a lump in the throat,. chronic throat clearing, choking episodes, or throat pain, or sometimes pulmonary symptoms such as chronic cough and asthma (Ohman et al. 1983; Olson 1986; Wiener et al. 1986; Ossakow et al. 1987; Flores et al 1981). Esophagitis and heartburn usually occur in patients with supine nocturnal reflux but patients with EEGR generally experience upright daytime reflux (Koufman 1991; Wiener et al. 1989). In addition, patients with EEGR tend to have UES dysfunction, whereas typical esophagitis patients have predominantly lower esophageal sphincter (LES) dysfunction. Because the patterns and mechanisms of reflux in patients with EEGR appear to differ significantly from those of patients with GERD, patients with EEGR are frequently mis-diagnosed because they do not have esophagitis and its symptoms (Wiener et al. 1989; Koufnan 1991).
Several studies comparing symptoms, diagnostic data, and results of treatment of patients with EEGR with normal controls and with GERD (i.e. esophagitis) patients have been reported (Koufman 1991; Wiener et al. 1986; Ossakow, et al. 1987; Wiener, et al. 1989). Based upon the fact that similar diagnostic methods were used for all of these studies, a comparative profile of the two conditions, EEGR and GERD, is shown in Table 1. These composite profiles are derived from the GERD literature and the inventor's data.
TABLE 1 ______________________________________ Summary of the Differences Between EEGR and GERD Patients EEGR GERD ______________________________________ Symptoms Heartburn 350% 89% Hoarseness 85% 3% Globus cough etc. 64% 6% pH-Monitoring Total abnormal 79% 100% Upright 88% 46% Supine 45% 100% Pharyngeal 50% 0% Other Diagnostic Tests (Abnormal %) Esophagoscopy & Bx 27% 100% Barium swallow 38% 68% Bernstein Test 30% 89% Esophageal acid-clearance 7% 70% UES manometry 50% 0% H2-antagonist therapy Failure rates 35% 10% ______________________________________
Since patients with EEGR have predominantly upright, daytime reflux, while GERD patients appear to have supine, nocturnal reflux, it is not surprising that the esophageal acid clearance of patients with EEGR is almost always normal, while for esophagitis patients, it is almost always prolonged. These findings help explain why patients with EEGR do not have esophagitis. The total esophageal acid-contact time is normal in the EEGR group but not in the esophagitis group.
In addition to the lack of heartburn and esophagitis, patients with EEGR appear to have a very high rate of medical treatment failure with H2-receptor antagonists, regardless of dose. Koufman (1991) reported that the failure rate for patients with EEGR treated with ranitidine (in doses of 600 mg to 1,200 mg per day) was 38%. This rate of medical failure is more than double that of similarly treated GERD patients. The high rates of failure of treatment for EEGR with H2-antagonists may be due to three interrelated variables: (1) H2-antagonists reduce gastric acidity, but do not abolish it; (2) although it is generally accepted that pepsin activity is acid-activated, 70% of peptic activity still remains at a pH greater than pH 4.0 (Piper and Fenton 1965); and (3) it appears that the mucosa of the larynx is its sole protective barrier against peptic injury. If the mucosa is injured then ulceration, granulation and perichondritis may occur. This damage appears to be principally through exposure to pepsin in the refluxate (Koufman 1991; Little et al. 1985; Lillemoe et al. 1982; Hirschowitz 1991; Johnson and Harmon 1986; Samloff and Taggart 1987). Thus EEGR that affects the larynx could be termed "peptic laryngitis".
Reliable diagnostic tools for GERD, and in particular EEGR, have been sought for decades. Since the 1960s, pH-monitoring has been used to diagnose GER, because the acid in the refluxate is easily measured by pH monitoring. For this reason, double-probe pH monitoring was developed.
Double-probe pH monitoring is a technique which simultaneously measures the pH in the esophagus and throat by using a device that consists of dual pH sensors which are imbedded in a single catheter such that when placed in the throat and esophagus one probe is in the distal esophagus five centimeters above the LES and the other probe is in the hypopharynx behind the laryngeal inlet just above the UES. Patients are monitored for 24 hours. A precipitous drop below pH 4 in the pharyngeal probe which is immediately preceded by a comparable drop in pH in the esophageal probe is considered to be evidence of EEGR.
While this pH based assay appears to be the most sensitive and specific yet available for the diagnosis of EEGR, it has several disadvantages. Calculations of its sensitivity range from only 68% to 80% (Koufman 1991). Possibly because EEGR is an intermittent, "life-style-related" disease (Koufman 1991, 1996), a 24 hour monitoring period is not always sufficient to determine if a patient has been experiencing previous EEGR events or if future events may occur. This problem is exasperated by the nature of the assay, which detects hydrogen ions, a small molecule that does not persist in the throat. In addition, this technique is highly invasive, i.e. approximately 12% of otolaryngology patients either refuse or cannot tolerate the procedure. Furthermore, significant dietary modifications occur during the pH monitoring procedure, which may artificially suppress reflux, thus making a negative result questionable. And finally, the method is expensive and hence has limited availability.
Pepsin, considered to be acid-activated, has been ignored as a diagnostic marker of GERD and EEGR because acid (pH) is quite easy to measure compared to pepsin. But as patients with EEGR commonly do not have esophagitis, or heartburn, pH monitoring and other diagnostic assays, which test for esophagitis, are often falsely negative in these patients. Several immunoassays have been developed to measure the levels of pepsinogens I and II in serum and urine in order to evaluate their potential as diagnostic markers of either gastrointestinal ulcers or stomach cancer (Waldum et al., 1979; Axelsson et al., 1982; Huang et al., 1987; Huang et al., 1988). It is contemplated that pepsin may enter the blood serum through GERD induced lesions in the throat. However, changes in pepsin levels in either the blood serum or urine due to GERD have never been evaluated nor have they been contemplated for their use as diagnostic markers of GERD or EEGR.
There is an immediate need, therefore, for a noninvasive, accurate and less expensive diagnostic method which can be Used to diagnose EEGR and monitor the progress of treatments for a variety of disorders of the throat and esophagus that are EEGR and GERD related.